UK NHS Online Clinic for August is CFS/ME & Fibromyalgia

Due to ongoing questions about the PACE Trial, the principle investigators (White, Sharpe, Chalder) have issued a response which the moderator is now referring people to whenever similar questions are asked on a thread:

I could say a lot about their statement, but I'll just pick up on some of the blindingly misleading information...

White et al said:

About six out of ten patients made a clinically useful improvement in both fatigue and functioning after CBT or GET.

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That is written ambiguously and it's misleading. It suggests that 60% of patients improved as a result of treatment with CBT or GET.
In fact an extra 16% of patients made a clinically useful improvement in both fatigue and functioning, when CBT or GET were added to SMC.

White et al said:

CBT and GET were also more effective in improving: general ability to do things

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Except for objectively measured physical disability (six minute walk test), for which there was no improvement when CBT was added to SMC, and possibly no clinically useful improvement when GET was added to SMC.
This statement also doesn't apply for employment, for which there were no improvements after CBT and GET were added to SMC.

White et al said:

We disagree with those people who are concerned that these improvements are somehow less valid since they relied on the subjective reports of patients rather than objective measures; we believe that the patient is the best judge of how unwell they are.

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Hold on, wasn't the basis of CBT, in the PACE Trial, that patients have 'false' illness beliefs, and so their judgement can't be trusted?
That was the whole point of CBT in the PACE trial. It was designed to address false illness beliefs.
So at what point does CFS/ME patients' judgement about their symptoms suddenly become valid? When they are very ill, moderately ill, or very well?
If CFS/ME patients are the "best judge of how unwell they are" (as the authors claim) when they are very ill, then on what basis is CBT prescribed? What is the point of it? Why would they want to change illness beliefs?

Anyway, after a year of training patients to think differently about their symptoms, and of training patients to interpret their symptoms in a different way, it is perverse that the authors are then only interested in testing patients' views about their illness, rather than assessing actual changes in physical disability. Such an approach only assesses how successfully the patients have been trained to interpret their symptoms differently, and it fails to assess what effect the therapies actual had on the illness.

By all objectively measured outcomes, CBT failed to make any difference.

The best thing i've seen about this is a remark someone made about CBT only changing the way people answer questionnaires - as someone who had 1-2 sessions of it I can tell you that is spot on! I don't know why they push GET/CBT so much but I suspect it is because they're scared of having nothing to offer patients in the way of help - in their mindset something (CBT/GET) is better than nothing, but in many peoples experience nothing would be the much preferred option. What i'd give for doctors to acknowledge the disease and say there is no treatment but then offer sensible advise like ''Take things easier and don't beat yourself up about it'', ''Only do what you feel you can'' instead of making ill people even more ill through silly therapies that have no medical evidence to back them up. I hope that when the true nature of the disease comes to light there are going to be some sincere apologies...

Can someone explain what these people gained from the PACE trial? Was it money or accolade? Surely it wasn't because they believed in the therapy

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They've staked their careers on it. Decades of time and who knows how much in funds wasted improperly treating patients in an attempt to prove their beliefs about ME/CFS are correct. Now they've got clinics, or teaching positions, etc, built upon it. If the bottom gets yanked out, everything comes tumbling down for them.

They've staked their careers on it. Decades of time and who knows how much in funds wasted improperly treating patients in an attempt to prove their beliefs about ME/CFS are correct. Now they've got clinics, or teaching positions, etc, built upon it. If the bottom gets yanked out, everything comes tumbling down for them.

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I think that if they released their original recovery criteria, then it would have shown a recovery rate of like 5%... a lot of GPs would have been pretty disgusted by the way CBT/GET had been over-promoted to them, and through them to their patients.

We went on to use a combination of self-reported measures (being within the population normal range for both fatigue and physical functioning, plus no longer meeting trial entry criteria, plus a self-rating of feeling “much” or “very much” better) to measure the numbers of patients who had recovered from their current ill-health, and found that both CBT and GET were about three times more likely to lead to recovery than the other two treatments.

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They fail to point out that: it was possible for participants to have deteriorated after treatment with CBT/GET (in terms of 'physical function') and be reported as 'recovered'; that participants could have had worse disability ('physical function') than when they entered the trial and be reported as 'recovered'; and that a 'recovered' participant can have severe physical disability ('physical function'); and that a 'recovered' participant could have physical impairment that was 'substantial' enough to qualify for a CFS diagnosis via the CFS empirical criteria (Reeves 2005.)

Severe disability and 'recovered', at the same time. An interesting concept!

Some people have criticised the trial for changing some things after we started the trial, such as how we analysed the results. This happens not infrequently in trials, and we stated at the very beginning that we would write a detailed statistical analysis plan as we went on. This was done in order to improve the analysis and interpretation of the data, and was completed before any outcome data were examined and approved independently by the two trial oversight committees. ​

I haven't followed the whole PACE debate - my brain isn't up to processing such a quantity of information - but I'm surprised at this statement that they said from the beginning that they'd write a statistical analysis plan as they went along and that it's not infrequently that planned analyses are changed.

On the contrary, I'd have thought it was extremely rare that a planned analysis was changed and I'm astonished they didn't plan all their analyses before they started work on a £4 million trial because, clearly, this wasn't a double-blind trial. It's not like drug vs placebo drug; everyone - patients and clinicians - knew what therapy they were getting and would have seen how things were going, even if they hadn't put numbers to it.

It would be interesting to put that statement about 'just business as usual' in a letter to the Lancet and see what other trialists think of it.

Some people have criticised the trial for changing some things after we started the trial, such as how we analysed the results. This happens not infrequently in trials, and we stated at the very beginning that we would write a detailed statistical analysis plan as we went on. This was done in order to improve the analysis and interpretation of the data, and was completed before any outcome data were examined and approved independently by the two trial oversight committees.​

I haven't followed the whole PACE debate - my brain isn't up to processing such a quantity of information - but I'm surprised at this statement that they said from the beginning that they'd write a statistical analysis plan as they went along and that it's not infrequently that planned analyses are changed.

On the contrary, I'd have thought it was extremely rare that a planned analysis was changed and I'm astonished they didn't plan all their analyses before they started work on a £4 million trial because, clearly, this wasn't a double-blind trial. It's not like drug vs placebo drug; everyone - patients and clinicians - knew what therapy they were getting and would have seen how things were going, even if they hadn't put numbers to it.

It would be interesting to put that statement about 'just business as usual' in a letter to the Lancet and see what other trialists think of it.

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There are some people who say that the code to do the statistical analysis should be pre-written at the start of the trial. Others suggest that the statistition should be blinded and allowed to check distributions to determine whether the proposed analysis is appropriate. I think there is some sense in this latter statement but that would only support small changes e.g. the statistical significance techniques used.

With PACE I believe there was quite a wholesale change in primary outcome measures and thresholds. I seem to remember reading documents from the european drug agency suggesting that the ethics committies reponsible for approving the trial in the first place should be notified of such changes.

I'm sorry if this question doesn't make sense. I have not been following the Pace trial but, did they account for the placebo effect?

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I think that is a complex question. They had what they would call a control group which was standard medical care and then three other treatment arms of standard medical care + (APT, CBT and GET). Hence I think they would claim to have controlled for the placebo effect.

However, they didn't control for different expectations for different treatments which seems to be a critism of many psych trials with a waitinglist or normal treatment vs additional treatment arm. Hence I think the answer is that they didn't control properly. With a drug trial expectations are the same since all patients believe that they are receiving the active treatment.

The other issue is around reporting. They largely rely on subjective measures (that is how patients report that they feel). Some time ago there was an asthma trial with some sham treatments and real treatments. I think subjective reports were similar from all patients but the objective tests showed that that only those receiving real treatments benefited. There is also evidence from other CBT/GET trials that subjective patient reports improve but activity measured by accelorometers doesn't. The one objective test that was included in PACE was a 6 minuite walking test which showed a small (but not clinically significant) improvement for GET but no other group.

Is "standard medical treatment" not just the usual "ignore, leave to rot on the compost heap"?

And does anybody know why normal pacing wasn't included (is the APT not just another version of graded exercise?)

They're so desperately keen to downplay any advantages of pacing....

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I think the significant difference between GET and APT is the way they were presented. GET was said to be a treatment that would make people better where as APT was intended to rest the body and support natural recovery.

The protocols for both were different for both but I tend to think the different expectations lead to different results.

Is "standard medical treatment" not just the usual "ignore, leave to rot on the compost heap"?

And does anybody know why normal pacing wasn't included (is the APT not just another version of graded exercise?)

They're so desperately keen to downplay any advantages of pacing....

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I too assumed that SMC meant 'standard medical treatment', but in the defence on talkhealth the psychs are calling it 'specialist medical treatment'.

Another crucial issue is that the CBT normally used in conjunction with GET is designed to persuade patients that they have incorrect illness beliefs, thus by inference it is designed to make them believe that exercise will help.

It would appear impossible to control for a placebo effect as the whole rationale of the treatment is based on one!

I too assumed that SMC meant 'standard medical treatment', but in the defence on talkhealth the psychs are calling it 'specialist medical treatment'.

Another crucial issue is that the CBT normally used in conjunction with GET is designed to persuade patients that they have incorrect illness beliefs, thus by inference it is designed to make them believe that exercise will help.

It would appear impossible to control for a placebo effect as the whole rationale of the treatment is based on one!

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My mistake they did call it specialist medical care but I don't think it was very specialist. Basically I think it included things like giving pain drugs along with being given their explanation of why you are ill.

I think that there would be also the element of wanting to please or not wanting to insult the practitioners that are spending time with you and have the expectation that what they are doing will show results.